CD19/CD20 bispecific chimeric antigen receptor (CAR) in naïve/memory T cells for the treatment of relapsed or refractory non-Hodgkin lymphoma.
Authors: Sarah Marie Larson, Christopher Walthers, Brenda Ji, Sanaz N. Ghafouri, Jacob Naparstek, Jacqueline Trent, Caitlin Harris, Mobina Khericha Gandhi, Thomas Schweppe, Martin S. Auerbach, Jonathan W. Said, Karla Nawaly, Monica Diane Mead, Sven De Vos, Patricia Young, Caspian Oliai, Gary J. Schiller, John Timmerman, Antoni Ribas, Yvonne Y Chen
Journal: Journal of Clinical Oncology (2022)

2543 Background: Although chimeric antigen receptor (CAR)-T cells produce impressive outcomes in B-cell malignancies, a substantial fraction of patients with relapsed/refractory B-cell leukemia and lymphoma treated with anti-CD19 CAR-T cell therapy (CART19) either do not respond to treatment or relapse, with poor CAR-T cell persistence or CD19 antigen escape being two key factors that limit durability of response. In order to address these factors, we initiated a clinical trial with naïve/memory T (T N/MEM ) cells engineered to express bispecific anti-CD19/CD20 CARs (CART19/20) (NCT04007029). Methods: This trial is a Phase 1, first-in-human, dose-escalation trial enrolling patients with relapsed or refractory follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle-cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Following lymphodepletion chemotherapy with fludarabine and cyclophosphamide, patients received CART19/20 cell doses ranging from 50 x 10 6 to 200 x 10 6 CAR-positive cells. The primary endpoint was to evaluate the safety of CART19/20 as measured by adverse events and dose limiting toxicities. Secondary endpoints were efficacy as assessed by disease response, progression-free survival (PFS), overall survival (OS), and CAR transgene persistence. Results: As of February 7, 2022, dose-escalation has been completed with 9 patients enrolled and 8 patients infused (3 FL, 4 DLBCL including 2 transformed follicular and 1 primary mediastinal B cell, and 1 MCL). with CART19/20 cells on this study. The median age at the time of CART19/20 infusion was 59 and median prior lines of therapy was 3.5. All patients had stage IV disease and 7 of 9 patients required bridging therapy. Grade-1 cytokine release syndrome (CRS) occurred in 6 of 8 patients, and no patient experienced immune effector cell-associated neurotoxicity syndrome ( ICANS). Among all patients, only one dose of tocilizumab was administered to one subject, and no steroids were given. With a median follow-up of 12 months from time of CART19/20 infusion (range: 4+ to 24+ months), 7 of 8 of patients remain in a complete remission. Median PFS and OS were not reached, and all patients with a complete remission demonstrate ongoing B-cell aplasia. Conclusions: This study demonstrates that CART19/20 cells are safe and effective in patients with relapsed/refractory NHL and potentially obviates the challenges of the commonest causes of relapse after CAR-T cell therapy by means of modifying T N/MEM cells and dual-antigen targeting, respectively. Given the strong safety and response observed, dose escalation was completed with the second dosing level (DL2) of 200 x 10 6 CAR-positive cells, and DL1 of 50 x 10 6 CAR-positive cells was chosen as the therapeutic dose for future trial expansion. Clinical trial information: NCT04007029.